The long-term objective of this Patient-Oriented Mentored Career Development Award (K23) is to support the career development of the candidate in functional neuroimaging and experimental therapeutics in mood disorders. This will be accomplished through a structured supervised research experience and formal instruction that will focus on the training areas of (1) Clinical Research Methodology, Biostatistics and Ethics;(2) Functional Neuroimaging Methodology;and (3) Affective and Cognitive Neuroscience. The specific objective of the proposed research strategy is to characterize the function of emotion-processing neural networks in vivo in patients with treatment-resistant depression (TRD), and to identify functional changes in these networks that are specific to rapid antidepressant response. Conventional antidepressant treatments are slow to result in therapeutic benefit, and 20-30% of patients with major depression fail to achieve an adequate therapeutic response (i.e., experience TRD). Recent findings of rapid and robust antidepressant effects of the anesthetic agent ketamine, a N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, present a unique opportunity to test hypotheses regarding the mechanisms of rapid-acting therapeutic action. The proposed research will utilize advanced cognitive neuroscience techniques and functional magnetic resonance imaging (fMRI) to investigate the specific functional contributions of key neural systems supporting emotion generation/regulation, including the prefrontal cortex (PFC), anterior cingulate cortex (ACC) and associated subcortical structures, in TRD and rapid antidepressant response to ketamine. TRD subjects will undergo fMRI at baseline (in the depressed state) and then again 24 hours following a single IV infusion of ketamine or a control treatment. The fMRI strategy will utilize both a well-validated probe of negative emotion bias (sad facial expressions), and a probe of emotion regulation (cognitive reappraisal), which specifically recruits PFC/ACC structures implicated in mechanisms of antidepressant action. This research will test specific hypotheses regarding the role of emotion generation (e.g. subcortical) and regulation (e.g. PFC/ACC) neural systems in the depressed state in patients with TRD, and changes in the function of these systems associated with changes in depressive symptoms resulting from ketamine. The skills and data acquired and research methods developed during the K23 award period will provide the candidate with the tools required to achieve the long- term goal of becoming an independent investigator in clinical neuroscience research in mood disorders. PUBLIC HEALTH RELEVANCE: Up to one-third of patients with major depression continue to suffer a high symptom burden despite an optimized treatment trial [e.g. they suffer treatment-resistant depression (TRD)], and symptom relief is slow even in patients who do respond. Therefore, rapidly acting, more effective treatments are urgently needed. The proposed research project aims to illuminate the functional brain mechanisms of rapid antidepressant response in patients with TRD, with the long-term goal of facilitating the identification of improved treatments for patients suffering from this disabling illness.